The ultimate goals of this program of investigations is the reduction of mortality and morbidity from clinical conditions commonly associated with respiratory insufficiency, particularly in diseases primarily involving the respiratory system. We propose to study certain aspects of the pathophysiology of respiratory insufficiency in order to enhance understanding of the mechanisms underlying important complications, and to develop new and improve existing methods of treatment which would reduce mortality from this disorder. The proposed investigations embrace a wide range of projects at the basic and applied levels concerned with the pathophysiology, evaluation, and management of states characterized by respiratory insufficiency. These studies comprise a multifaceted program and range from investigations on isolated tissues, such as studies of the metabolism of isolated blood vessels, and studies in intact animals, to improvement in the bedside management of critically ill patients. The specific aims of the six projects comprising this grant are as follows: (1) To study certain aspects of the regulation of cerebral blood vessels in anesthetized and unanesthetized animals in relation to the abnormalities which might be expected to occur in patients with respiratory insufficiency and to investigate changes in cerebral blood flow and metabolism in patients with respiratory insufficiency in the course of treatment for this disorder. (2) To study the mechanism of the pulmonary vasoconstrictor effect of hypoxia in unanesthetized animals with normal lungs or with lungs which have developed experimental emphysema and to study the effect of treatment on the pulmonary hemodynamics in patients with respiratory insufficiency. (3) To develop a method based on measurement of peak airflow acceleration for the reliable and rapid detection of small changes in resistance of small airways. (4) To study the effect of alterations in blood gas tensions and pH comparable to those seen in patients with respiratory insufficiency on experimentally produced arrhythmias.